Pharmaceutical aerosol formulations of formoterol and beclometasone dipropionate

a technology of beclometasone and formoterol, which is applied in the direction of organic active ingredients, respiratory disorders, medical atomizers, etc., can solve the problems of ostwald ripening, the effect of reducing the solubility

Active Publication Date: 2011-04-07
CHIESI FARM SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0031](d) HFA 134acharacterized in that HFA 134a is the sole propellant and the salt of formoterol is suspended in a micronized form while the corticosteroid is fully dissolved, exhibit improved stability.
[0034]Finally, the present invention provides the use of a corticosteroid for aerosol formulation for inhalation comprising a pharmaceutically acceptable salt of formoterol or a solvate thereof as an active ingredient and a mixture of HFA134 and ethanol as vehicle, for decreasing the solubility of said salt of formoterol in said vehicle wherein the vehicle has a polarity expressed as dielectric constant εm comprised between about 9.5 and about 11.0, preferably between about 9.5 and about 10.5.

Problems solved by technology

However, although it has the apparent pH adjusted according to the teaching of WO 01 / 89480 for improving its chemical stability, due to the limited stability of formoterol in solution, said formulation can be stored for no longer than 15 months at a refrigerator temperature (from +2 to +8° C.) and for no longer than 5 months at room temperature.
These stability features are not optimal, in particular in sub-tropical and tropical countries.
On the other hand, the amount of ethanol useful for solubilizing the corticosteroid may not be appropriate or optimal for ensuring the physical stability of a suspended drug.
The effect of Ostwald ripening may be particularly severe for a drug such as formoterol which needs to be formulated in low doses.

Method used

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  • Pharmaceutical aerosol formulations of formoterol and beclometasone dipropionate

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0111]The solubility determination of BDP in the HFA134a / ethanol mixtures was determined according the method reported in Gupta A et al, J. Aerosol Medicine, 2003, 16(2), 167-174, slightly modified as follows.

[0112]Vials that contained excess BDP were prepared at 2%, 3%, 4% and 5% ethanol in HFA134a. After equilibration, the samples were filtered though a 0.2 μm PTFE filter coupled inline with Presspart standard C126 canisters fitted Bespak EPDM with a dip tube. The results are reported in the plot of FIG. 1, from which the BDP solubility can be extrapolated.

example 2

[0113]The solubility of formoterol fumarate dihydrate in HFA134a:ethanol 97.3:2.7 (w / w) in the presence and in the absence of 0.1% w / w BDP was estimated according to the method of Example 1. The formoterol fumarate dihydrate solubility at 20° C. without BDP turned out to be about 0.005 μg / μl corresponding to about 0.0005% w / w. After addition of 50 μl of 0.1 w / w BDP solution, it decreases more than half, i.e. to 0.002 μg / μl corresponding to about 0.0002% w / w.

example 5

[0116]An aerosol formulation was prepared starting from micronized formoterol fumarate dihydrate obtained by milling having a MMD comprised between 2 and micron and beclometasone dipropionate as commercially available. Said formulation has the following composition:

Formoterol fumarate dihydrate0.0095% w / wBeclometasone dipropionate 0.079% w / wEthanol  2.7% w / wHFA134to 100%

This formulation was filled into an aluminum canister under pressure and fitted with a metering valve having a 63 μl metering chamber. It is suitable for delivering 6 μg formoterol and 50 μg beclometasone dipropionate per actuation.

[0117]The aerosol performances were assessed using an Andersen Cascade Impactor according to according to the procedure described in the European Pharmacopoeia 6th edition, 2009 (6.5), part 2.09.18. Quantification of beclometasone dipropionate (BDP) and formoterol fumarate dehydrate (FF) was performed using a HPLC method. The following parameters were determined:

[0118]i) delivered dose is ...

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Abstract

Pharmaceutical formulations comprising beclometasone dipropionate and a salt of formoterol exhibit improved stability and are useful in pressurised metered dose inhalers (pMDIs).

Description

CROSS REFERENCES TO RELATED APPLICATIONS[0001]This application claims priority to European Patent Application No. 09172083.9 filed on Oct. 2, 2009, which is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The present invention relates to pharmaceutical formulations for use in the administration of medicaments by inhalation. In particular, the present invention relates to pharmaceutical formulations for use in pressurized metered dose inhalers (MDIs). The present invention also relates to methods for the preparation of said pharmaceutical formulations and to the use thereof in therapy.[0004]2. Discussion of the Background[0005]Pressurized metered dose inhalers (pMDIs) are well known devices for administering pharmaceutical active ingredients to the respiratory tract by inhalation. They consist of containers containing multiple doses, e.g., tens or even hundreds of doses, and each of these doses is delivered by a suitabl...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/12A61P29/00A61P11/00A61P11/06A61M11/00
CPCA61K9/008A61K31/167A61K31/573A61K45/06A61K2300/00A61P11/00A61P11/06A61P29/00A61K9/00A61K9/12A61K31/537
Inventor BRAMBILLA, GAETANO
Owner CHIESI FARM SPA
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